PT91689B - PROCESS FOR THE PREPARATION OF AN ADHESIVE BACTERICIDE COMPOSITION - Google Patents

Abstract

An antibacterial pressure sensitive adhesive composition suitable for medicinal application to an infection prone skin area comprising a mixture of a solid hydrophobic acrylic adhesive, silver sulfadiazine and inter-ally crosslinked sodium carboxymethylcellulose and its method of use.

Description

Scope of the Invention

The present invention relates to a bactericidal adhesive composition suitable for medical application. More particularly, the invention relates to a hydrophobic, bactericidal adhesive with an effective acrylic base that includes silver sulfadiazine as a bactericidal agent and internally crosslinked sodium carboxymethylcellulose as release aid.

Background of the Invention

Various adhesive compositions for medical applications are known in U.S. Patent No. 3,339

545 describes an adhesive composition comprising a mixture

of one or more hydrocolloids that are swellable with water or soluble in water and polysobutylene. ^The latent reser US 4,393,150 has a polyisobutylene, polybutene, butyl rubber adhesive, reinforcing fibers, filler material and zinc oxide mixed with heating and laminates to obtain a thin sheet. Schonfeld in latent US No. 4 140 115 presents adhesive dressing-type articles that minimize skin attack in applications that provide a support material, for example a plasticized film support, having a pressure sensitive adhesive composition, insoluble in water coated thereon. composition that includes about 4 - 20% by weight of an unreacted polyol uniformly dispersed therein.

For certain medical uses, for example, treatment of burns, it is often desirable to apply medications to the injured area with various medications including bactericidal agents. Although bactericidal agents and other drugs can be applied directly to the injured area, it is often convenient to apply the medicine to the part of the dressing that comes in contact with the affected area, in this way, the medicine is automatically and uniformly applied to the affected area when applied. a dressing on him.

U.S. Patent No. 4,340,043 to Seymour discloses adhesive-coated sheet materials that incorporate up to about 25% by weight of bactericidal substances in the adhesive coating to kill bacteria in a wound and that cover the surrounding skin area. Various bactericidal agents are mentioned including metal salts such as neomycin, bactericides such as chlorhexidine and its salts, iodophoric quaternary ammonium compounds, and preferably silver sulfadiazine. Seymour teaches that application of up to 25%, preferably up to 15%, by weight of silver sulfadiazine in a finely divided form to adhesive compositions provides a bactericidal action. Seymour says that proportions up to 1% can be used

silver sulfadiazine but recognizes that in order to obtain effective bactericidal properties the appropriate range must start at about 5% silver sulfadiazine. The effective amount of silver sulfadiazine needed by Seymour, ie 5% or more, is unreasonably high for reasons of safety and cost.

U.S. Patent No. 4,551,490 to Doyle et al. refers to pressure sensitive adhesive compositions suitable for various medical applications and which are resistant to erosion of moisture and biological fluids. Doyle et al. refers to useful compositions as a form of a homogeneous mixture of a mineral oil, one or more polyisobutylene or mixtures of one or more polyisobutylene and an elastomer such as butyl rubber, block or radial styrene copolymers, hydrocolloid gums soluble in water, water-swelling cohesion reinforcing agents and an adherence-enhancing agent. Doyle et al. refer to the use of adhesive reinforcing agents intumescible with water that provides resistance to erosion by biological fluids to adhesive compositions. Sodium-crosslinked carboxymethylcellulose is identified as a cohesive reinforcing agent intumescible with suitable water, Doyle et al. also note that small amounts, i.e. less than 5% by weight of the adhesive composition, may contain other optional ingredients for example for the treatment of burns, active ingredients such as silver sulfadiazines and other silver compounds which may also be included . Doyle et al. they do not discuss or consider the efficiency of silver sulfadiazine incorporated in adhesive dressings for the treatment of burns.

Although several compositions are known which may optionally contain bactericidal agents such as silver sulfadiazine, superior adhesive compositions are necessary incorporating bactericidal agents such as silver sulfadiazine which can provide a more efficient and effective bactericide in an injured area.

It is, therefore, an object of the present invention to provide acrylic adhesive compositions containing silver sulfadiazine which provide a more efficient and effective bactericidal action with small amounts of the active ingredient than have been practiced up to now. The effective use of smaller amounts of silver sulfadiazine reduces the cost and increases safety while maintaining the therapeutic value of the products obtained from them.

Summary of the Invention The aforementioned object of providing more efficient and effective activity has now been achieved by improving the release of silver sulfadiazine from acrylic based adhesives according to the compositions and processes of this invention.

In accordance with the objectives of the invention, which are hereby incorporated and fully described, the invention comprises a pressure sensitive adhesive antibacterial composition suitable for medical application to a skin infection comprising a mixture of a solid hydrophobic acrylic adhesive, in the bactericidal amount effective amount of silver sulfadiazine, and an effective amount of internally cross-linked sodium carboxymethylcellulose to release silver sulfadiazine from the adhesive mixture in order to provide an effective bactericidal action to the application area. In the preferred practical embodiments of the invention] the adhesive compositions comprise by weight of the total compositions, from 40% to 50% of solid hydrophobic acrylic adhesive, 0.5 to 3.0% of silver sulfadiazine to 10%, more preferably of about 2 to 3% of internally cross-linked sodium carboxymethylcellulose.

The invention also comprises a method of reducing bacteria on an infected skin area comprising applying a pressure sensitive bactericidal adhesive comprising a mixture of hydrophobic adhesive,

in the effective bactericidal amount of silver sulfadiazine an amount of internally crosslinked sodium carboxymethylcellulose sufficient to make an effective bactericidal amount of silver sulfadiazine available for the skin infection area in order to reduce the bacteria present in that area.

Detailed Description of the Preferred Embodiments of the Invention

Reference will now be made in detail to the current preferred embodiments of the invention, with examples that are illustrated in the following example section. It should be understood that the following general and detailed description is exemplary and explanatory only and is not to be construed as restricting the invention as claimed.

The pressure sensitive bactericidal adhesive compositions of the invention are suitable for various medical applications, particularly, for use as wounds and burns. The pressure sensitive compresses and wound compresses of the invention should be applied to injured areas or burns of the skin where the protective epidermis has been removed or damaged thereby exposing the inner layers of the skin to possible infections by external bacterial and microbial sources. This area of skin to which the dressing or adhesive is applied is defined for the purposes of the invention as an area of infectious skin ”. Infectious areas of skin may also include areas subject to erosion, skin problems or degenerative skin diseases that can also affect the area of infectious skin.

Pressure sensitive adhesive compositions can be prepared in the form of adhesive strips or dressings comprising support materials including but not limited to plasticized film supports such as plasticized vinyl chloride, as well as woven and woven fabrics, paper bodies and metal sheets and

expanded materials such as expanded polyurethane.

The present invention is not to be understood as having any particular mechanism or mode of action for the migration of the silver sulfadiazine active ingredient from the adhesive layer to the infected skin areas. The present invention is based on the discovery that the inclusion of internally cross-linked sodium carboxymethyl cellulose in an acrylic based adhesive that substantially improves the bactericidal efficiency of surprisingly small amounts of silver sulfadiazine incorporated therein. The internally cross-linked sodium carboxymethyl cellulose promotes the efficiency of silver sulfadiazine by facilitating the release or migration of silver sulfadiazine from the active mixture and increases its availability to the infected skin area. It is thought that the addition of internally cross-linked sodium carboxymethylcellulose transports moisture from the wound area and the atmosphere to the adhesive matrix in order to facilitate its disintegration thereby releasing the silver sulfadiazine and therefore dramatically increasing the bactericidal efficiency of the combination.

The adhesive bactericidal compositions of the invention are particularly advantageous since only small amounts of silver sulfadiazine should be present in the adhesive composition to promote effective bactericidal action on the infected skin area. The effective bactericidal action is defined as a reduction of bacteria in the order of at least 100 (log 2.0) depending on the unprotected area of the skin. The bactericidal adhesive compositions of the invention demonstrated a reduction in batteries of more than 200 (log 2.30) to more than 300.

Preferred amounts of sulfadia. silver zinc are about 0.5 to 3.0% by weight of the total adhesive composition, more preferably about 1.0%. Smaller amounts of silver sulfadiazine give rise to cost and safety benefits of the products they incorporate

the compositions and methods of the present invention.

The amounts of internally cross-linked sodium carboxymethylcellulose that are effective in increasing the bactericidal effect of silver sulfadiazine is at least 1% by weight, more preferably from about 2 to about 3% of the total solvent adhesive mixture and up to an amount which is practical to provide sufficient release amounts to the adhesive without adversely affecting the adhesion and cohesion properties of the compositions. A preferred upper limit will be about 10% by weight of the adhesive mixture comprising the adhesive solids and silver sulfadiazine.

The currently preferred internally crosslinked carboxymethyl cellulose is sold under the trade name of Ac-Ui-Sol by the company PMC Corporation. This internally crosslinked sodium carboxymethylcellulose, also referred to as modified cellulose gum, is a cellulose ether produced by reacting alkaline cellulose with sodium monochloroacetate under specified reaction conditions to produce an internal or intrachain crosslinking. Normal sodium carboxymethylcellulose is generally soluble in water but the internally crosslinked form is essentially insoluble in water. The internally crosslinked product is highly absorbent and is known as an effective disintegrant. Comparative tests of internally cross-linked sodium carboxymethylcellulose in relation to other water-soluble or water-absorbent polymers and disintegrants reveal that internally cross-linked sodium carboxymethylcellulose is considerably more effective in improving bactericidal efficiency of identical amounts of silver sulfadiazine within adhesive mixtures. The results of this comparison test are presented in the example sections below.

preferred bactericidal agent according to the invention is silver sulfadiazine in a finely divided form. The size of the sulfadiazine particles

silver is generally less than about 20 micrometers in diameter and most of them are less than 5 micrometers in diameter and are embedded in the mixture of the adhesive layer. Particles that are finely divided and less than 20 micrometers in diameter are preferred since the small size contributes to a more effective dispersion and greater solubility of silver sulfadiazine in wound fluids.

Although adhesive solids based on rubber elastomers that include a polyol are satisfactory adhesives, the preferred adhesive masses according to the invention are based on acrylic systems. These acrylate masses essentially consist of an important amount of the medium chain alkyl acrylate monomer and optionally small amounts of cohesion-inducing short chain monomers, in combination with a small amount of a polymerizable silyl alkoxy crosslinking monomer in the polymerization system. acrylate.

Useful average chain length alkyl acrylate monomers are those that have an average of about 4-12 carbon atoms in the alcoholic radical and include: butyl, hexyl, 2-ethylhexyl, octyl, decyl acrylates , and dodecyl and similar products, alone or in combination with each other or with higher or lower alkyl acrylates. The medium chain acrylate monomer is present in the adhesive copolymer of this invention in an important amount of weight of the total monomers.

Cohesion-inducing short-chain monomers are generally chosen from vinyl acetate, methyl acrylate, acrylic acid, diacetonaacrylamide, N-t-butylacrylamide, and the like.

The alkoxy silyl crosslinking monomers comprise an alkoxy silyl alkyl group and an unsaturated terminal functional group copolymerizable with the other monomers. This functional end group is preferably an acrylate or a substituted acrylate group as for examplej ||

-OCCH = CH

0.

li or -OCC (CH ₃ ) = CH ₂

The crosslinkable polymerisable alkoxy silyl alkyl groups that have been found to be particularly effective are those that have the general formula:

in which R 'and R ”are CH ^ or CH ^ CI ^ e and R is chosen from the group consisting of CH ^, GHg, CH ^ O, and CH ^ CH ^ O and en is an integer from 0 to 8. 0 A preferred silyl crosslinking monomer is 3-methacryloxypropyltrimethoxy silane.

The amount of the silyl crosslinking monomer to be included in the copolymer depends on the exact constituents of the copolymer and the desired degree of crosslinking. The silyl crosslinking monomer will generally include in amounts up to about 0.005 to 0.1 or more parts by weight of the total monomers with an amount of about 0.001 to 0.05 parts by weight being preferred. It is made in U.S. Patent No. 2. 4 140 115 a general description of acrylate polymers and other useful adhesive compounds such as adding polyols to reduce skin irritation. The full description of this patent is hereby incorporated by reference to provide additional teachings of examples of adhesive components of the invention.

In adhesive mass compositions based on an acrylate resin, it is usual practice to use a solvent coating technique in order to apply the adhesive mass to the article or support material to be coated.

In well-known conventional techniques, an organic solvent such as cyclohexane or ethyl acetate is used.

Suitable support material can be a plasticized polyvinyl chloride support material, a polyvinyl chloride and polyacetate copolymer, a polyvinyl chloride and acrylonitrile copolymer and self-supporting film materials, as well as fabric or paper on which the paper can be used alone or as a vehicle for a plasticized organosol.

It is thus obvious that compositions and methods of the invention are effective in promoting the bactericidal activity of silver sulfadiazine in adhesive mixtures, particularly acrylic adhesive mixtures, due to the presence of internally crosslinked carboxymethylcellulose in fulfilling the objects of the invention.

Examples

The invention will now be illustrated with examples. The examples are not intended to limit the scope of the present invention. In connection with the detailed and general description presented above, the examples provide a better understanding of the present invention and define a process for the preparation of compositions of the invention.

The following examples represent preferred embodiments of the compositions, processes and methods of the invention that meet the stated objectives for the invention. The starting materials and starting reagents used in the examples in which the method of preparation is indicated are commercially available from known sources such as chemical warehouses.

Example I

Preparation of an Adhesive Dressing Containing a release biologically active ingredient

Below is a formulation

typical containing silver sulfadiazine (SSD) at 1% by weight of total solids in a solvent based on a hydrophobic acrylic adhesive:

2674 Acrylic Adhesive (about 45 $ solids) SSD

Internally crosslinked carboxymethylcellulose (Ac-Di-Sol brand from EMC).

acrylic adhesive is prepared

Ingredients:

A. 2-Ethylhexyl acrylate

B. Vinyl acetate

C. Silano

D. Ethyl acetate

E. Lauroyl Peroxide

Weight in grams

985.56

4.58

9.86

1000.00 as follows:

Parts by Weight

550.0

150.0

0.10 (0.09 ml)

612.5

3.13

Substances A - D are loaded in a 2 liter bottle. Heat to 72 ° C in a nitrogen atmosphere. The nitrogen feed is cut off, 2.50 parts by weight of reagent E are added and heating is continued until an exothermic reaction occurs. The exothermic reaction (82-84 ° C) is controlled by cooling the outer walls of the flask. At the end of the exothermic reaction, heating is resumed under the flow for 3 hours. An additional 0.63 parts by weight of Reagent E is added and reflux is continued for 2 hours. Cool and discharge.

The additives (SSD and carboxymethyl cellulose) are mixed together or are then slowly added to a stirred solution of the adhesive. After 30 minutes of stirring, the dispersion is homogeneous and is coated on a release paper to obtain a wet thickness of 5mm and air dried. The adhesive film is coated by transfer to a polyurethane film.

adhesive film is uniform in appearance, clear in color and without any undispersed particles apparent.

Comparison Examples II-IX

Eight comparison examples are prepared comprising water-soluble polymers or water absorber added to the acrylic adhesive together with 1% SSD and coated on a polyurethane film, according to the procedures of Example I, as well as, examples not using polymeric additive and without SSD or polymeric additives.

Examples II-VII

The procedure described for Example I follows, with the exception of replacing Ac-Li-Sol with the following polymer additives listed:

Example II

2.1% AVICEL water-insoluble micro crystalline cellulose obtained from EMC and 2.1% from Ac-Di-Sol.

Example III

2.1% of a hydroxypropyl ether of water-soluble cellulose of the brand KLUCEL supplied by Hércules.

Example IV

2.1% of a NATRASOL water-soluble cellulose hydroxyethyl ether obtained from Hercules,

Example V

2.1% of an insoluble cellulose sodium carboxymethyl ether was CMC water obtained from Hercules.

Example VI

2.1% of an EXPLOTAB water-insoluble potato starch sodium carboxymethyl ether obtained from iendend and 2.1% of water-insoluble cellulose powder from SOLKA-P1OC obtained from iiendall.

Example VII

2.1% of a hydroxypropyl ether of soluble methyl cellulose was METHOCEL water obtained from Dow and 2.1% of Ac-Di-Sol.

Comparison Examples VIII and IX! Example VIII is prepared as described above, except that only an acrylic adhesive is used and without SSD or polymer additive. Example IX includes only the acrylic adhesive and SSD.

Involuntary bactericidal efficiency test of Examples I-IX

Compresses of the Examples were tested

I-IX containing a content of 1% SSD (there was no SSD included in Ex. VIIl) for the determination of its bactericidal activity against Ps. aeruginosa present in full thickness excisions of totally contaminated guinea pigs. Microbial sampling of wounds 24 hours after treatment revealed the following average Ps log reduction. aeroginous viable when compared to untreated controls (See Table 1 below).

Method

Pseudomonas aeruginosa is the test organism used in this experiment. The preparation of the organism for inoculation in wounds consisted of the culture of Soy Broth Trypticase for 24 hours at 35 ° C. The cells were collected by centrifugation, washed with sterile saline, and made up to the original volume.

The cells were then diluted 1-1,000 and the last dilution was used for inoculation.

ANIMAL MODEL ·

Totally thick circular excisions are made in the middle of the back with approximately 4 cm surgically in anesthetized guinea pigs and in which the hair has been removed, weighing between 400 and 500g. The wounds are inoculated with 0.01 milliliters of a Ps suspension. aeruginosa and wounds are treated with the compress designated for each group, (secured with an ELASTIKON adhesive tape obtained from John son 1 Johnson). After a 24-hour treatment period, the wounds are sampled by rubbing with cotton wool. Each piece is placed in 10 milliliters of a 1% solution of sodium citrate and vortexed. Serial dilutions were obtained and plated in Soybean upright plates and incubated for 48 hours at 35 ° C. After 48 hours the plates are examined and the number of CFUs (colony forming units) is counted.

Results

The results obtained are shown in Table I following J

Table 1

Ex. Composition

I SSD + Ac-Di-Sol

Logarithmic reduction of Ps. aeruginous

2.49

Comparative Examples

II SSD + AVICEL + Ac-Di-Sol 2.08 III SSD + KLUCEL LP 2.03 IV SSD + NATROSOL 25OL 1.66 V SSD + CMC 7LXE 1.06 SAW SSD + SXPLOTAB + SOLKA-ELOC 1.20 VII SSD + METHOCEL + Ac-Di-Sol 1.50 VIII SSD 0.77 IX Without SSD Control

In summary, it was determined that only the adhesive additive of Example I, consisting of only Ac-Di-Sol, an internally crosslinked modified cellulose gum obtained from EMC and SSD, was highly effective in promoting the release of SSD from a hydrophobic acrylic adhesive, thus resulting in a significantly increased reduction in the concentration of the microorganism present.

The scope of the present invention is not limited by the description, examples and suggested uses and modifications can be made without departing from the spirit of the invention. For example, other additives can be included in the adhesive mixture of the invention, such as analgesic compositions, other medicaments, or other additives that can increase the cohesive strength of the adhesive mixture and thus improve other desirable properties.

The application of the compositions and methods of the invention and the products obtained by it can apply to

various fields as it will be today and in the future recognized by experts. The application of the products of the invention to medical uses can be achieved by any suitable therapeutic method such as those known to those skilled in the treatment of wounds and burns. Thus, it is intended that the invention includes the modifications and variations of this invention as long as they are within the scope of the appended claims and their equivalents.

Claims (1)

- Rrocesso for the preparation of a pressure sensitive adhesive bactericidal position characterized by incorporating 40 to 50% of a solid hydrophobic acrylic adhesive, 0.5 to 3.0% of silver sulfadiazine and 10% of sodium carboxymethylcellulose internally cross-linked. 2. The process according to claim 1, characterized in that silver sulfadiazine is present in a proportion of about 1% by weight of the composition. - 3§ _ Flow according to claim 1, characterized in that the internally cross-linked sodium carboxymethyl cellulose is present in a proportion - 16 of about 2 to 3% in weight of the composition. - 4th Process according to claim 1, characterized in that the silver sulfadiazine is present in a proportion of about 1% and the internally cross-linked sodium carboxymethyl cellulose is present in a proportion of about 2 to 3% by weight of the composition. _ 5â _ Process according to claim 1, characterized in that the internally cross-linked sodium carboxymethyl cellulose is a product of the reaction between alkaline cellulose and sodium monochloroacetate. The applicant claims the priority of the North American application submitted on September 12, 1988, under the serial number 24-3,389.